Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway
Name
journal.ppat.1007298.pdf
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4.22 MB
Format
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Checksum (MD5)
f519e62330e1477d5356cd5e0bb9064e
Author(s)
Ye, Weijian
Chew, Marvin
Hou, Jue
Lai, Fritz
Leopold, Stije J.
Loo, Hooi Linn
Ghose, Aniruddha
Dutta, Ashok K.
Chen, Qingfeng
Ooi, Eng Eong
Date Issued
October 2018
Journal
PLOS Pathogens
Publisher
Public Library of Science
Citation
Ye, Weijian, Marvin Chew, Jue Hou, Fritz Lai, Stije J. Leopold, Hooi Linn Loo, Aniruddha Ghose, et al. “Microvesicles from Malaria-Infected Red Blood Cells Activate Natural Killer Cells via MDA5 Pathway.” Edited by Martin Goodier. PLOS Pathogens 14, no. 10 (October 4, 2018): e1007298.
Version
Final published version
Abstract
Natural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1371/journal.ppat.1007298
